Gene Variants In Adiponectin And Its Receptors As Risk Factors For Metabolic And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$534,107.00
Summary
Obesity has a major impact on the development of metabolic syndrome (MetS), type 2 diabetes (T2D), and cardiovascular disease (CVD). It is important to identify the molecular links between obesity and these conditions. Adiponectin, an adipocyte-specific hormone, is a likely molecular candidate because of its pleiotropic metabolic actions. We will investigate the role of adiponectin, the variants within its gene ADIPOQ, and that of its two receptors, in the development of MetS, T2D, and CVD.
IGF BINDING PROTEIN-2 A MODULATOR OF IGF ACTION IN DEVELOPING AND NEOPLASTIC NEURONAL CELLS.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged ....In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged brain, and in tumours, plays a key role on the surface of neurons in regulating IGF availability. We have shown that IGFBP-2 associates with a specialised protein on the nerve cells, where it is further processed to smaller fragments. We believe that these processes are reactivated following brain injury or in cancer states where IGFBP-2 is highly abundant. We propose to determine how IGFBP-2 influences IGF action on the nerve cell surface, and to further ascertain the function of each step in this process. We will achieve this by examining the effects of the mutated version of IGFBP-2, designed to either prevent its binding to the cell surface or its processing to smaller fragments. We will use various human and mouse nerve cell for these studies, which will not only provide greater understanding of the regulation of IGF availability to developing brain cell, but also point to how these processes may be involved in enhancement of recovery from injury or stroke, or possibly in acceleration of tumour growth. The finding of this study will offer the potential for new and exciting treatment designed to alter the function of the IGF system, to either make it more active in response to brain injury or stroke, or less active in brain tumours.Read moreRead less
The Regulation Of Insulin Action In Liver And Skeletal Muscle By Protein Kinase C Epsilon
Funder
National Health and Medical Research Council
Funding Amount
$647,604.00
Summary
We have identified an enzyme, protein kinase C epsilon, which has a major negative impact on the control of blood glucose levels. We will now examine the mechansisms by which it affects insulin action in liver and muscle, two major target tissues of the hormone responsible for glucose disposal. This work is expected to validate PKCepsilon or its downstream effectors as therapeutic targets in the treatment of the insulin resistance which accompanies obesity and Type 2 diabetes.
Understanding The Cause And Consequence Of Impaired Insulin Secretion In The NZO Mouse A Model Of Diabetes.
Funder
National Health and Medical Research Council
Funding Amount
$711,224.00
Summary
Type 2 diabetes is a major health problem affeting over 1 million Australians. A key feature of this disease is reduced secretion of the pancreratic hormone insulin which results in high blood sugar levels. We are using a naturally occurring animal model of diates called the NZO mouse to understand why the pancreas secretes less insulin and the consequences of this defect. This project has the potential of providing better therapeutic strategies for patients with Type 2 diabetes.
A Longitudinal Study Of Nerve Morphology In Diabetic Neuropathy Using Novel Non-invasive Ophthalmic Surrogate Markers
Funder
National Health and Medical Research Council
Funding Amount
$540,372.00
Summary
This research project will use two new ophthalmic instruments - the corneal confocal microscope and non-contact corneal aesthesiometer - to directly monitor changes in corneal nerves and corneal sensitivity, over a 5 year period, in diabetic patients suffering from a painful condition of the arms and legs known as diabetic neuropathy. This study will generate important new information that could allow diabetic doctors to more accurately monitor the progression of the disease.
Novel Approaches To Risk Stratification In Patients With Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
75% of the mortality in adults with Type 2 diabetes is due to a cardiac event. Early detection and treatment of cardiac disease is paramount in improving health outcomes. An echocardiogram is an accurate and non-invasive identification of cardiac dysfunction. We will assess the prognostic value of echocardiography and novel plasma markers in patients with diabetes. Our results may lead to new management and screening guidelines for heart disease in diabetes.
Dilinoleoyl Phosphatidic Acid As A Novel Mediator Of Insulin Resistance In Muscle
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
We have identified a novel fat molecule in muscle which may play an important role in causing insulin resistance during obesity, a major factor in the development of Type 2 diabetes. We will now examine whether depletion of this molecule, dilinoleoyl-phosphatidic acid, can improve insulin action in muscles and in obese mice, and investigate the mechanisms by which it may act. This work may indicate new strategies for the treatment of diabetes.
An Examination Of The Contribution Of Visceral Adiposity To Insulin Resistance In Humans.
Funder
National Health and Medical Research Council
Funding Amount
$335,800.00
Summary
The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has particular importance. Visceral fat cells are differen ....The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has particular importance. Visceral fat cells are different to other fat cells; they are very metabolically active and 'spill out' fatty acids indiscriminately contributing to insulin resistance in liver and muscle; they also produce hormones which may modify the action of insulin. We will study people undergoing abdominal surgery. Participants will be (1) normal weight and sensitive to insulin, (2) abdominally overweight and insulin resistant, (3) insulin resistant with Type 2 diabetes. We will document abdominal fat, circulating lipid and hormone levels and insulin action. At surgery fat biopsies will be obtained from (a) inside the abdominal cavity, (b) the fat layer under the abdominal skin and (c) fat in the buttock. The activity of a large number of genes in the fat tissue will be assessed in 8 subjects using DNA array (4 each from Groups 1 and 2). Then a small number of genes will be selected on the basis of different activity in visceral fat from buttock fat, and between insulin sensitive and insulin resistant people. The activity of these genes will be determined in all subjects in the 3 groups. We anticipate identifying a few (perhaps 3) genes whose activity is closely associated with insulin resistance and will examine their capability to block insulin action in a series of animal and cellular studies. These studies should identify specific mechanisms by which visceral fat creates insulin resistance. This would be an important step towards prevention and improved medication for Type 2 diabetes.Read moreRead less
The Role Of Hypoxia Inducible Factor 1a In Beta-Cell Function And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$362,303.00
Summary
HIF1a is a gene which our preliminary data shows is needed for normal beta-cell function and insulin secretion. When beta-cells cannot release enough insulin, blood sugar levels rise, and diabetes develops. This research plan will look at the effects of deletion of HIF1a and of increasing HIF1a to see how this affects function of beta-cells and - or diabetes development. This work may show that HIF1a is a potential therapeutic target for the treatment of diabetes in humans.
Effect Of Oral Glutamine On GLP-1 And Insulin Secretion And Glycaemia In Humans.
Funder
National Health and Medical Research Council
Funding Amount
$397,444.00
Summary
Diabetes is an ever increasing problem with serious complications. We will investigate whether glutamine, one of the most common amino acids (protein building blocks) in the body, has a beneficial effect on blood glucose and insulin levels in the body in people who have type 2 (non-insulin dependent) diabetes. If so, glutamine supplementation may represent a novel, cheap and palatable way of improving outcomes and preventing the development of complications in people with type 2 diabetes.